1-methyl equilenin compounds and process for making



United States Patent The present invention relates tocyclopentanoperhydrophenanthrene compounds. More particularly thepresent invention relates to novel estrogens and the production thereofand especially 1-methyl estrogens.

It has been previously set forth in the prior literature, as for exampleInhoifen, Angew. Chem. Vol. 59, p. 207, 1947, that the 1,4-diene-3 onesof the steroid series readily undergo aromatization of ring A with aconcomitant migration of the angular methyl group to yield so-calledl-methyl phenols, as for example l-methyl estradiol, 1- methyl estrone,etc. These compounds were insoluble in alkali and devoid of estrogenicactivity.

In accordance with the present invention various compounds have beenprepared probably possessing the 1- methyl configuration and having verysubstantial estrogenic activity. Fmther, in contrast to the previouslydisclosed compounds the new compounds are soluble in alkali, havedifferent melting points and other properties, and upon admixture withthe previously known compounds have clearly demonstrated theirdifierence as by depression of the melting points.

In application Serial No. 152,498, filed March 28, 1950, now Patent No.2,705,237, a novel process for the production of estrogens andintermediates is disclosed. Among the estrogen intermediates disclosedin this application are the novel A -3-ketosteroids. In particular,application Serial No. 152,498 discloses Al,4,6-3-ketosteroids which maybe exemplified by the following formula:

wherein A may be C=C or CH-OR and R may be hydrogen, a lower alkylgroup, as for example methyl or ethyl or an aromatic group such asbenzyl or a residue of a lower fatty acid or an aromatic acid, as forexample acetic acid, propionic acid or benzoic acid. It has been foundin accordance with the present invention that A 3-ketosteroids, andparticularly compounds of the character described, upon treatment with acatalyst capable of promoting the dienonephenol rearrangement, as forexample acetic acid/anhydride or propionic acid/anhydride together withparatoluene sulfonic acid will rearrange to produce novel l-methyl-A-estrogens which exhibited estrogenic properties.

It has been further discovered in accordance with the present inventionthat the l-methyl-A -estrogens thus produced could be readilyhydrogenated utilizing a hydrogenation catalyst to produce in good yieldl-methyl estrogens, as for example l-methyl estrone or l-methylestradiol, these novel l-methyl estrogens together with their ester andether derivatives exhibiting definite estrogenic properties and beingsoluble in dilute alkali.

Ithas further been found in accordance with the present invention thatthe Lmethyl-M-estrogehs could be de-" hydrogenated in the-presence of asuitable catalyst to produce the novel l-methyl equile'n-in andderivatives thereof.

The production of the novel l-methyl-M-estrogen compounds of the presentinvention may be exemplified by the following equation:

CH3 CH: CH: A B

I CH3 I heat acetic anhydrlde P--toluena sullonic acid /sfi nificatlonCH5! In the above equation'A'may represent the groups previ-. ously setforth. R5; represents the residue of acetic acid or in the eventpropionicanhydrideis used the residue of propionic acid. B representsC=O 'and COR and R, may be a lower alkyl group, as for example methyl orethyl or an aromatic group such as benzyl or the residue of a lowerfatty acid or an aromatic acid as for example acetic acid, propionicacid or benzoic acid. D represents C=O or C-OH.'. I I v In practioingthe dienone phenol rearrangement above set forth a mixture of trie'nonewith paratoluene sulfonic acid and the acetic or propionic anhydridecould be heated on a steam bath for a suitable period of time, as forexample five hours. The resultant solution was then cooled andhydrolyzed by agitation with water and the crystaline product thusprecipitated was filtered, dried and recrystalized from a suitablesolvent, as for example an alcohol such as methanol. The products couldbe then further recrystallized from similar organic solvents forpurification. The reaction proceeded both. with the esters of the A-3-ketosteroids and also with the free compounds, i.e. those compoundswherein A is COH, since those compounds were esterified under theconditions of the reaction. For example the product of the dienonephenol rearrangement of A -androstat1ien-3,l7-dione using aceticanhydride was l-methyl-A -dehydroestrone acetate and the product of thedienone phenol rearrangement of both A androstatrien-l7-ol-3-one and its-17- acetate, was 1-methyl-M-dehydroestradiol-3,17-diacetate. The estersthus produced could then be converted to the free compoundsas bysaponification with an alcoholic solution of a suitable alkali metalhydroxide by refluxing the ester therewith. Sulfonic acid could be alsoused as a catalyst in place of the toluene sulfonic acid for therearrangement of the alcohols and derivative compounds, i.e. where A wasC-OR, and in this case the reaction was carried out at room temperature.

The 1methyl-A -dehydroestrone compounds may also be reduced utilizinglithium aluminum hydride to the corresponding l-methyl'A-dehydroestradiol compounds. This reaction may be performed generally bydissolving the l-methyl-M-dehydroestrone acetate for example in a drysolvent, i.e. preferably anv ether solvent, and refluxing the same withaluminum hydride. The l-methyl-A -dehydroestradiol which is thusproduced is entirely similar to that produced by the dienone phenolrearrangement previously set forth.

The l-rnethyl-A compounds produced in accordance with the foregoingreaction can be readily hydrogenated to the corresponding l-methylestrogen in accordance with the following equation:

CH; B

catalytic 11,0 hydrogenation CH; 0 Ha OH! on.

saponification Rxo HO wherein R B and D indicate the same groupspreviously set forth.

The hydrogenation reaction above set forth preferably takes place in thepresence of a suitable catalyst such as palladium-on-charcoal or othersuitable hydrogenation catalyst. For example, when a solution of1-methyl- A -dehydroestrone acetate in ethyl acetate in the presence ofa 10% palladium-on-charcoal catalyst was shaken in an atmosphere ofhydrogen for approximately two hours or until the hydrogen take-upcorresponded to 1 mol, 1- methyl estrone acetate was produced. Thel-methyl estrone acetate could then be saponified to produce 1- methylestrone.

The I-methyI-A -dehydmestrogens can also be dehydrogenated to producethe corresponding novel l-methyl equilenin compounds in accordance withthe following reaction:

In the above reactions R B and D represent the same groups as previouslyset forth.

In the above reaction the preferred dehydrogenating agent is seleniumdioxide. However, other common dehydrogenating agents, such aspalladized charcoal, other precious metal catalysts, chloranil and thelike may be used. In general the l-methy-A -dehydroestrogen is dissolvedin a suitable solvent such as acetic acid or dioxane and refluxed for ashort period of time 'with the catalyst under an atmosphere of nitrogen.The reaction mixture is then filtered to remove the selenium and thefiltrate diluted with water. The resultant product is then filtered andrecrystallized from a suitable solvent, such as methanol. The estersproduced may then be saponified as previously set forth.

The following specific examples serve to illustrate the presentinvention but are not intended to limit the same:

Example I A mixture of 15.5 g. of A androstatrien-3,l7-dione, 3.90 g. ofp-toluenesulfonic acid and 600 cc. of acetic anhydride was heated forfive hours on a steambath. The cooled solution was hydrolyzed byswirling with water, the crystalline product was filtered, dried andrecrystallized from methanol; yield, 12.85 g. (72%), melting point147-149 C. Further recrystallization from the same solvent gave pure1methyl-M-dehydroestrone acetate with a melting point of 152-153 C. [a]94 (dioxane); ultra-violet maxima at 222 mu (log E 4.444) and 264 mu(log E 3.93).

Analysis.Calculated for C H O C, 77.75; H, 7.46. Found: C, 78.09; H,7.53.

Example II Saponification of the acetate of Example I was accomplishedin 97% yield by refluxing with 2% methanolic sodium hydroxide solutionfor one hour. Two recrystallizations from methanol gave1methyl-M-dehydroestrone with a melting point of 250-252 C. [a] 87.7(chloroform) 76.8 (dioxane); ultra-violet maxima at 228 mu (log E 4.49),268 mu (log E 3.90) and 306 mu (log E 3.28).

Example III A mixture of 2.7 g. of A -androstatrien-l7-ol-3-onel7-acetate, 100 cc. of acetic anhydride and 1 g. of p-toluene sulfonicacid was subjected to the same procedure as in Example I. 2.89 g. (95%)of l-methyl-A -dehydroestradiol-3,l7 diacetate was produced with amelting point of ll0-ll3 C. Recrystallization from hexane gave in 71%yield the purified compound with a melting point of 116-117" C. [a] l49;ultra-violet maxima at 222 mu (log E 4.46) and 264 mu (log E 3.96).

Analysis-Calculated for C H O C, 74.97, H, 7.65. Found: C, 74.76, H,7.38.

This same rearrangement was also effected utilizing the free 17 hydroxycompound which was acetylated under the conditions of the rearrangementto produce the same product. The same reaction was also carried oututilizing 10% by weight of sulfuric acid as the catalyst instead of thep-toluene sulfonic acid. When sulfuric acid was used as the catalyst,the reaction was preferably carried at room temperature.

Example IV Saponification of the diacetate of Example 111 by refiuxingwith 2% methanolic sodium hydroxide solution similarly to Example IIproduced in substantially quantitative yield lmethyl-M-dehydroestradiolhaving a melting point of -132 C. This melting point was unchanged afterseveral recrystallizations from either hexane acetone or dilute methanol[a] 124- (chloroform), 134 dioxane; ultra-violet maxima at 226 mu (log E4.57) and 266 mu (log E 3.95).

Analysis.-Calculated for C H O C, 80.24, H, 8.50. Found: C, 80.48, H,8.50.

The phenol produced was readily soluble in 2N aqueous sodium hydroxideand was benzoylated by the Schotten-Baumann method to producel-methyl-M-dehydroestradiol-3-monobenzoate having a melting point ofl46- C. after recrystallization from hexane-acetone, [a] l23.

Analysis.Calculated for C H O C, 80.42, H, 7.27. Found: C, 80.35, H,7.19.

Example V A solution of 2 g. of lmethylM-dehydroestrone acetate ofExample I in 600 cc. of dry ether was refluxed with 1 g. of lithiumaluminum hydride for thirty minutes. After the usual work-up, there wasobtained 1.54 g. (88%) of 1methyl-M-dehydroestradiol having a meltingpoint of 129-132 C., which gave no depression on admixture with thesample prepared according to Example IV and possessed the same rotationand spectrum.

' Example VI A solution of 4 g. of 1-methyl-A -dehydroestrone acetatehaving a melting point of 147l49 C. of Example I in 60 cc. of ethylacetate was shaken in the presence of hydrogen with 800 mg. ofpalladium-on -charcoal catalyst for two hours, at which time thehydrogen uptake corresponded to one mol. After filtration, evapora-Example VII Alkaline saponification of the l-methylestrone acetate ofExample VI in accordance with procedure of Example II led inquantitative yield after recrystallization from methanol tol-methylestrone, having a melting point of 250-252 C. [a] +257(chloroform), +246 (dioxane); ultra-violet maximum at 282 mu (log E3.26) and minimum at 250 mu (log E 2.51). The so-called lmethylestrone,described in the literature, had a melting point of 249251[a] +27l.6 anda mixture of the two specimens melted at 212223 C. In contrast to thelatter substance, l-methylestrone of the present invention dissolved onwarming in 5% aqueous alkali and exhibited approximately one-half theestrogenic potency of estrone in rats.

Analysis.-Calculated for (319112402: C, 80.24; H, 8.50. Found: C, 80.05;H, 8.50.

Example VIII Hydrogenation of the A -dehydro diacetate of Example III inthe manner described in Example VI, in ethyl acetate solution with 10%palladium-on-charcoal catalyst (barium sulfate supported catalyst wasequally satisfactory) alforded 81% of shiny, prismatic blades (frommethanol) of l-mcthylestradiol-Ii,17-diacetate with a melting point of178-180 C. [u] +111; ultra-violet maximum at 268 mu (log E 2.53) andminimum at 252 mu (log E 2.44).- The so-called l-methylestradiol 3,17-diacetate described in the literature had a melting point of 138.5-139".

Example IX l-methylestradiol, prepared either by saponification of itsdiacetate of Example VIII or by hydrogenation of 1-methyl-A-dehydroestradiol of Example IV in accordance with the procedure ofExample VI, was obtained from etherhexane as a microcrystalline powder,which shrank at 95 C. and melted at 1l0ll6 C. [a] l46; ultra-violetmaximum at 284 mu (log E 3.28) and minimum at 250 mu (log E 2.25). Thephysical constants of this alkali-soluble estrogenically potent phenolare in complete contrast to those reported for the so-calledl-methylestradiol: insoluble in alkali, crystallizes readily, meltingpoint 235.5-236.5 [a] +185 (dioxane).

Analysis.Calculated for C H O C, 79.67; H 9.14. Found: C, 79.87; H,9.36.

Example X The 3,17-dipropionate of the l-methylestradiol of Example IXwas isolated in nearly quantitative yield on heating l-methylestradiolfor one hour with propionic anhydride and pyridine; colorless platesfrom methanol, having a melting point of 125.5-127" C. [OL:|D20+1O1-5;

6 ultra-violet; maximum at 268 mu (log E 2.58) and minimum at 254 mu(log E 2.45).

Analysis.-Calculated for C H O C, 75.34; H, 8.59. Found: C, 75.16; H,8.63.

Example XI A solution of 1 g. of l-methyl-A -dehydroestrone acetate ofExample I in 20 cc. of glacial acetic acid or dioxane was refluxed forten minutes with 0.17 g. of freshly sublimed selenium dioxide undernitrogen. After filtration of selenium, the solution was diluted withwater, the pink solid (0.90 g., melting point -165 C.) was filtered andrecrystallized from methanol, yielding 0.62 g. of l-methylequileninacetate as colorless crystals with a melting point of l7l 172.5 C. [a]+113.'

Analysis.-Calcu1ated for C H O C, 78.23; H, 6.88. Found: C, 78.54; H,6.98.

Example XII Alkaline saponification of the acetate of Example XIafforded l-methylequilenin, which after recrystallization from aqueousmethanol had a melting point of 215-217 C. [a] +138.'5 (dioxane). Theultraviolet spectrum closely resembled that of equilenin.

Example XIII A mixture of 1 g. of 1-methyl-n -dehydroestradiol3,17-diacetate, 0.15 g. of selenium dioxide and 15 cc. of glacial aceticacid was refluxed for fifteen minutes. After filtering, pouring intowater and recrystallizing from hexane-acetone, colorless plates of1-methyl-17-dihydroequilenin 3,17-diacetate with a melting point of136l37 C. [u] 16 (chloroform) was obtained. Saponification andrecrystallization from aqueous methanol or hexane-acetone yielded1-methy1-17-dihydroequilenin- 17,3, having a melting point of 225227 C.[a] +33 wherein D is selected from the group consisting of -O and CH-OHwhich comprises dehydrogenating a compound of the following formula:

/B CE; I

wherein B is selected from the group consisting of 0:0 and CHOR and R isselected from the group consisting of a lower alkyl group, a benzylgroup, the residue of a lower fatty acid and the residue of benzoicacid, and R is selected from the group consisting of the resi-- due ofacetic acid and the residue of propionic acid with.

selenium dioxide and thereafter saponifying the dehydro-- genationproduct with an alkali metal hydroxide.

2. A process, for the production of l-methyl equilenin esters, whichcomprises dehydrogenating l-ethyl- A -dehy;

droestrone. estergwithselenium dioxide,

3. A process for the production ofi .1-methylegpilenin, which comprisesdehydrogenation l-methyl-A -dehydroestrone esters with selenium dioxideand thereafter saponitying. the. l-methylequilenin. esterj thus formedwith an alkalimetal' hydroxide.

4. A processfor the production of 1-methyl-17-dihydro,

equilenin esters, which comprises dehydrogenating, 1-methyl-AF-dehydroestradiol, esters with. selenium dioxide. 5. A processfor the production. of1-methyl-17-dihydro equilenin, which comprisesdehydrogenating. with selenium dioxide 1:methyl-A -dehydrostradio1.esters, to. form an ester of .1-methyl-17-dihydro equileninandthereafter saponifying". said ester with an alkali, metal hydroxide.

6. A new compound comprising. 1.-methy1 equilenin acetate having amelting pointof 171-172.5 C.

7. A new compound comprising l-methyl equilenin having amelting point of2152'17..C.

8. A new compound, comprising 1-methyl-1.7-dihydroequilenin-3,l7-diacetate. having a melting point of. 136- 137 C.

9. A new compound, comprising 1-methyl-17-dihydro equilenin-175 having amelting point of 225-227 C.

10. l-methyl equilenin compounds selected from the group consisting ofI-methyl equilenin, lower fatty acid esters of l-methyl equilenin, thebenzoate of l-methyl equilenin, lower alkyl ethers of l-methylequilenin, 1-. methyl-17-dihydrofequilenin, lower alkyl ethers offlmethyl-17-dihydro-equilenin, 3,17-di lower fatty acid'es ters of1-methyl-17-dihydro-equilenin, 3-mono lower fatty acid esters ofl-methyl-l7-dihydro-equilenin, the3,17-di benzoate of l-methyl-17-dihydro-equilenin, and the 3- mono benzoate of1-methyl-17-dihydro-equi1enin.

References Cited in the file of this patent UNITED STATES PATENTSRuzicka Dec. 23, 1941 Inhoifen Apr. 28, 1942 Wettstein et al. July 22,1958 OTHER REFERENCES Bachmann et al.: J.A.C.S., vol. 62, pp. 824-39(1940).

Inhoffen Angewandte Chem. 53 (1940), pp. 471-475.

Badger: J. Chem. Soc., vol. 1947, pp. 764-6 (1947).

Heer et al.: Helv. Chim. Acta., vol. 30, pp. 550-8 (1947).

InhofienAngewandte Chem. 59 (1947), pp. 207-212.

McKenzie et al.: J. Biol. Chem, vol. 173, pp. 271-81 (1947).

Fieser & Fieser: Natural Products Related to Phenanthrene, 1949, p. 329.

Djerassi et al.: I.A.C.S., vol. 72, pp. 4534-40 (1950).

1. A PROCESS FOR THE PRODUCTION OF COMPOUNDS HAVING THE FOLLOWINGFORMULA:
 6. A NEW COMPOUND COMPRISING 1-METHYL EQUILENIN ACETATE HAVINGA MELTING POINT OF 171-172.5*C.